CN103958490B - 2-position alkyl or the substituted tanshinone derivative of aromatic radical, and its preparation method and application - Google Patents

2-position alkyl or the substituted tanshinone derivative of aromatic radical, and its preparation method and application Download PDF

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CN103958490B
CN103958490B CN201280056730.2A CN201280056730A CN103958490B CN 103958490 B CN103958490 B CN 103958490B CN 201280056730 A CN201280056730 A CN 201280056730A CN 103958490 B CN103958490 B CN 103958490B
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tanshinone
derivant
pharmaceutically acceptable
alkyl
acceptable salt
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CN103958490A (en
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荣风光
徐荣臻
谢福文
赖洪喜
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Bunsen Pharmaceutical (Shanghai) Co., Ltd.
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Hangzhou Bensheng Pharmaceutical Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J73/00Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/003Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom

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Abstract

The invention belongs to natural drug and medicinal chemistry art, it is specifically related to novel 2 alkyl of formula I or aromatic radical substituted Tanshinone I derivant or its pharmaceutically acceptable salt, the method preparing these compounds, the pharmaceutical composition comprising this compound and the purposes in preparing antitumor drug thereof.Work as Z=R, be 2 substituted Tanshinone Is of alkyl;Work as Z=Ar, be 2 substituted Tanshinone Is of aromatic radical;Work as Z=Het, be 2 heteroaryls or the substituted Tanshinone I of heterocyclic radical.

Description

2-position alkyl or the substituted tanshinone derivative of aromatic radical, and preparation method thereof and Application
Technical field
The invention belongs to natural drug and medicinal chemistry art and relate to novel tanshinone derivative, particularly 2-position alkyl Or aromatic radical substituted Tanshinone I derivant, and prepare the method for these compounds, the compositions comprising this compound and Prepare the purposes in antitumor drug.
Background technology
Tanshinone I (Tanshinone I), is again Radix Salviae Miltiorrhizae quinone I, chemical formula (1,6-dimethyl-phenanthro-[1,2-b] furan- 10,11-diketone), it is extracted from root and the stem of labiate Radix Salviae Miltiorrhizae (Salvia miltiorrhiza Bge).Tanshinone I, its Pharmacological action is extensive, and Clinical practice scope is very big, can be used for treating coronary heart diseases and angina pectoris, myocardial infarction, viral myocarditis, The treatment of the diseases such as arrhythmia, cerebrovascular, cerebral blood supply insufficiency, cerebral thrombosis, cerebral infarction, hepatitis, tumor, hypertension. Therefore, scientists has carried out substantial amounts of research to following various tanshinone derivatives.
Owing to the water solublity of Tanshinone I is very poor, its in vivo bioavailability the lowest, so there being scientist to attempt Radix Salviae Miltiorrhizae Ketone I carries out structural modification, to improve its water solublity and bioavailability, expands the medical value of Tanshinone I.(Qin Yinlin. Radix Salviae Miltiorrhizae Ketone I derivant and application [P] the CN 1837199A.2006 in pharmacy thereof;Qin Yinlin. Tanshinone I derivant and in pharmacy In application [P] CN 1837200A.2006;Du Zhiyun etc. tanshinone derivative and preparing aldose reduction enzyme inhibitor pharmaceutical In application [P] CN 101012270A.2007).
Tanshinone I has certain antitumor action.Have been reported that by observing Tanshinone I to Hep G2 cells in vitro and body The impact of the many indexes of interior experiment, comprehensive descision its whether there is anti-tumor activity.Vitro Experimental Results shows, Tanshinone I The propagation of Hep-G2 cell can be suppressed.Additionally, tumor bearing nude mice tumor suppression test result indicate that Tanshinone I can suppress lotus tumor naked The growth of Mus tumor, i.e. also has function of tumor inhibition on live body.(Zheng Guocan, Li Zhiying. TANSHINONES HepG2 Carbazole alkaloid The experiment in vitro research of effect. modern medicine, 2004,32 (15): 296-298;Zheng Guocan, Li Zhiying. Tanshinone I antitumor is made With and the experimentation of mechanism of action. practical tumor magazine, 2005,20 (1): 33-35).
It addition, studies have reported that the external propagation on SGC-7901 gastric adenocarcinoma cells of Tanshinone I and the impact of apoptosis.Real Issuing after examination and approval existing, Tanshinone I has obvious inhibitory action, and its suppression to the growth of the SGC-7901 human gastric adenocarcinoma of In vitro culture Cell grows within the specific limits, increases and inhibitory action enhancing with the concentration of Tanshinone I. (Zhou Xiaoli etc. Tanshinone I is to people Gastric adenocarcinoma cells SGC-7901 propagation, the impact of apoptosis. modern medical oncology, 2011,19 (3): 423-427).
Although a lot of with bioactive research to the structural modification of Tanshinone I, but there is not yet good water solubility, toxicity The synthesis of the antitumor tanshinone compound that low and biological activity is high and the report of application.
Summary of the invention
An object of the present invention be to provide the 2-position alkyl of logical formula (I) or aromatic radical substituted Tanshinone I derivant or Its pharmaceutically acceptable salt:
Work as Z=R, for Formulas I-1, the 2-position substituted Tanshinone I of alkyl;Working as Z=Ar, for Formulas I-2,2-position aromatic radical is substituted Tanshinone I;Work as Z=Het, for Formulas I-3,2-position heteroaryl or the substituted Tanshinone I of heterocyclic radical,
Wherein R is selected from replacement or unsubstituted C1-C18Alkyl, replacement or unsubstituted C2-C18Alkenyl or alkynyl, replacement or Unsubstituted C3-C7Cycloalkyl or cycloalkenyl group;Ar is selected from replacement or unsubstituted aryl;Het is selected from replacing or unsubstituted miscellaneous Ring group or heteroaryl;Wherein said replacement be selected from lower group one or more substituent groups replace: halogen, amino, C1-C6Take For amino, nitro, cyano group, C1-C6Alkoxyl, sulfydryl, C1-C6Alkylthio group or water soluble functional group, Ar can also be by C1-C6 Alkyl replaces.
The two of the purpose of the present invention are to provide the preparation present invention and lead to 2-position alkyl or the substituted TANSHINONES of aromatic radical of formula (I) The method of I derivant:
The 2-position alkyl of the present invention or aromatic radical substituted Tanshinone I derivant (I) can be by two-step reactions as shown in above formula Produce.First Tanshinone I and bromide reagent are reacted generation 2-bromine Tanshinone I intermediate;Again by 2-bromine Tanshinone I intermediate and phase The organic boronic answered or borate in the presence of a catalyst, occur carbon-carbon bond formation reaction to generate 2-position alkyl or aromatic radical take The Tanshinone I derivant (I) in generation, in its Chinese style (I), Z is identical with the definition in logical formula (I) above, the most further by institute Obtain compound derivatization and obtain other formulas (I) compound.
The three of the purpose of the present invention are to provide the pharmaceutical composition comprising the compounds of this invention, and described pharmaceutical composition includes At least one the compounds of this invention, and optional pharmaceutically acceptable excipient.
The four of the purpose of the present invention are to provide the compounds of this invention or the pharmaceutical composition that comprises this compound is preparing medicine Purposes in thing, particularly antitumor drug.Correspondingly, the present invention provides a kind of method treating tumor patient, including giving Need the compound of at least one present invention of the bacterium for the treatment of.Described tumor is in particular selected from leukemia, multiple Property myeloma, lymphoma, hepatocarcinoma, gastric cancer, breast carcinoma, cholangiocellular carcinoma, cancer of pancreas, pulmonary carcinoma, colorectal cancer, osteosarcoma, melanin Tumor, human cervical carcinoma, glioma, nasopharyngeal carcinoma, laryngeal carcinoma, the esophageal carcinoma, middle ear neoplasms, carcinoma of prostate etc..
The invention still further relates to the compound of the present invention for treating tumor.
The five of the purpose of the present invention are to provide the midbody compound of following formula:
Detailed description of the invention
The present invention relates to the novel 2-position alkyl of logical formula (I) or aromatic radical substituted Tanshinone I derivant or its pharmaceutically Acceptable salt.
Work as Z=R, for Formulas I-1, the 2-position substituted Tanshinone I of alkyl;Working as Z=Ar, for Formulas I-2,2-position aromatic radical is substituted Tanshinone I;Work as Z=Het, for Formulas I-3,2-position heteroaryl or the substituted Tanshinone I of heterocyclic radical,
Wherein R is selected from replacement or unsubstituted C1-C18Alkyl, replacement or unsubstituted C2-C18Alkenyl or alkynyl, replacement or Unsubstituted C3-C7Cycloalkyl or cycloalkenyl group;Ar is selected from replacement or unsubstituted aryl;Het is selected from replacing or unsubstituted miscellaneous Ring group or heteroaryl;Wherein said replacement be selected from lower group one or more substituent groups replace: halogen, amino, C1-C6Take For amino, nitro, cyano group, C1-C6Alkoxyl, sulfydryl, C1-C6Alkylthio group or water soluble functional group, Ar can also be by C1-C6 Alkyl replaces.
Formula (I) compound of the present invention has active anticancer.
According to one preferred embodiment of the invention, described R is not the substituted C of carboxyl1-C18Alkyl or carboxyl are substituted C2-C18Alkylene, and R is not amino or the substituted methyl of substituted-amino.
According to presently preferred embodiment, described water soluble functional group selected from hydroxyl, multi-hydroxy alkoxy, Saccharide residue, carboxyl, sulfonic group, phosphate, multi-hydroxy alkoxy carbonyl, Carboxyalkoxy, carboxyalkyl formyloxy, Qi Zhongsuo State the alkoxyl in group and alkyl each has 1-8 carbon atom.
According to one preferred embodiment of the invention, described Z represents aryl or heterocyclic aryl.According to one spy of the present invention The most preferred embodiment, described Z represents phenyl.
According to presently preferred embodiment, described R is C1-C12Alkyl, preferably C1-C6Alkyl, more preferably first Base.
According to one preferred embodiment of the invention, described Ar is the substituted phenyl of the phenyl of halogen substiuted, preferably chlorine.
According to presently preferred embodiment, described Ar is C1-C6The substituted phenyl of alkyl, preferably methoxyl group Substituted phenyl.
According to a particularly preferred embodiment of the present, compared with the Tanshinone I (TA) that natural extract separates, this Bright formula (I) compound adds water soluble group, also improves active anticancer, the active anticancer of particularly preferred compound simultaneously Even improve several times.Such as, such compound is following formula (I) compound, and wherein said Ar is multi-hydroxy alkoxy Substituted phenyl, described multi-hydroxy alkoxy is preferably 3-7 carbon atom, more preferably glycerol residue;Or take for saccharide residue The phenyl in generation, preferably glucose residue are substituted.It is following formula (I) compound at the most such compound, wherein said Ar For the substituted phenyl of carboxyl, sulfo group or phosphate.
In one embodiment, the present invention relates to the compound of logical formula (I), wherein R, Ar, Het take from corresponding boron Acid or borate.
The part preferred 2-position alkyl of the present invention or aromatic radical substituted Tanshinone I derivant are as follows.These are real Execute and only enumerate that the present invention will be further described, the scope of the present invention is not constituted any restriction.
The part data of above-claimed cpd are listed in the table below:
In another embodiment, following logical formula (I) compound specifically preferred according to the invention:
As used herein, term " alkyl " refers to containing the straight or branched alkyl specifying carbon number, such as C1- C18Alkyl, C1-C12Alkyl, C1-C6Alkyl, C1-C5Alkyl, C1-C4Alkyl, C1-C3Alkyl etc..The example of alkyl includes but does not limits In methyl, ethyl, n-pro-pyl, isopropyl, the tert-butyl group, n-pentyl, n-hexyl and n-octadecane base.
Term " thiazolinyl " refers to containing the straight or branched alkylene specifying carbon number, such as C2-C18Thiazolinyl, C2-C12 Thiazolinyl, C2-C6Thiazolinyl, C2-C5Thiazolinyl, C2-C4Thiazolinyl, C2-C3Thiazolinyl etc..C2-C18The example of alkylene includes but not limited to ethylene Base, pi-allyl and octadecylene alkyl.
Term " C3-C7Cycloalkyl or cycloalkenyl group " refer to the alkyl with the 3-7 unit single loop system of saturated or unsaturated ring. C3-C7Cycloalkyl or cycloalkenyl group can be cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclopropanyl and cyclohexene Base.
Term " aryl " refers to the monocyclic carbocyclic ring aromatic radical containing 6-14 (such as 6-12,6-10) carbon atom or condenses Or many homocyclic aromatic groups of non-condensed, in the case of many carbocyclic rings, as long as a carbocyclic ring is fragrance.Aryl also include with The aryl that heterocyclic radical condenses.The example of described aryl has phenyl, xenyl, naphthyl, 5,6,7,8-tetralyls, 2.3-dihydrobenzene And furyl etc..
Term " heteroaryl " refers to contain 1-4 hetero atom (such as 1,2,3 or 4 hetero atoms) in ring as ring members Aromatic group.Hetero atom refers to nitrogen, oxygen or sulfur.Heteroaryl can be the bicyclic heteroaryl with 5-7 annular atoms, or There is the bicyclic heteroaryl of 7-11 annular atoms.As long as a ring is aromatic heterocycle in described bicyclic aryl, another can Being fragrant or non-aromatic, containing heteroatomic or without heteroatomic.The example of heteroaryl has such as pyrrole radicals, pyrazoles Base, imidazole radicals, oxazolyl, pyridine radicals, pyrimidine radicals, furyl, thienyl, isoxazolyl, indyl etc..
Term " heterocyclic radical " refers to containing non-aromatic as ring members of 1-4 hetero atom (such as 1,2,3 or 4 hetero atoms) Fragrant cyclic group.Hetero atom refers to nitrogen, oxygen or sulfur.Heterocyclic radical can be monocyclic heterocycles base (the such as 4-7 with 4-8 annular atoms Ring, 5-7 ring, 5-6 ring), or there is the bicyclic heterocyclic radical of 7-11 annular atoms.The example of heterocyclic radical has azetidin Base, pyrrolidinyl, pyrrolinyl, tetrahydrofuran base, dihydrofuran base, piperazinyl, piperidyl, morpholinyl, thio-morpholinyl, four Hydrogen pyranose, tetrahydro-thienyl etc..
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " alkyl-substituted amino " refers to-N-alkyl.
Term " alkoxyl " refers to-O-alkyl.
Term " alkylthio group " refers to-S-alkyl.
Term " multi-hydroxy alkoxy " refers to by the alkoxyl of 2 or more than 2 hydroxyl replacements, preferably former containing 3-7 carbon The alkoxyl of son, preferably dihydroxy propoxyl group, trihydroxy butoxy, tetrahydroxy amoxy etc..
Term " saccharide residue " refers to remove remaining saccharide residue after a hydrogen atom from sugar hydroxyl.Described sugar is preferably 3- The monosaccharide of 7 carbon atoms, such as triose, tetrose, pentose, hexose or heptose.
As used herein, the example of term " pharmaceutically acceptable salt of formula (I) compound " is by being formed pharmaceutically The acylate that the organic acid of acceptable anion is formed;These acylates include but not limited to toluene fulfonate, first Sulfonate, malate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbic acid Salt, lactate, alpha-ketoglutarate and α-glycerophosphate;Also suitable inorganic salt can be formed;These inorganic acid salts include but It is not limited to hydrochlorate, sulfate, nitrate, bicarbonate and carbonate, phosphate, hydrobromate, hydriodate etc..
Pharmaceutically acceptable salt can use standardization program well known in the art to obtain.Such as, by by enough alkalescence Compound and provide the suitable acid reaction of pharmaceutically acceptable anion to generate.
Terms used herein " is treated " and is generally referred to obtain the pharmacology needed and/or physiological effect.This effect is according to complete Fully or partially prevent disease or its symptom, can be preventative;And/or according to partially or completely stable or cure diseases And/or due to the side effect of disease generation, can be curative." treatment " used herein covers and appoints patient disease What treatment, including: (a) prevents easy infection disease or symptom but is not diagnosed to be disease or the symptom that ill patient is occurred; B the symptom of () suppression disease, i.e. stops it to develop;Or the symptom of (c) alleviation disease, i.e. cause disease or symptom to be degenerated.
The compound of the present invention can be prepared according to conventional organic chemical synthesis method.Such as, the formula (I) of the present invention is changed Compound can be prepared by following method:
The Tanshinone I that the 2-position alkyl of formula (I) or aromatic radical substituted Tanshinone I derivant can be separated by natural extract (TA) first through bromination reaction, 2-bromine Tanshinone I intermediate is generated;This intermediate again with corresponding organic boronic or borate, In the presence of catalyst, carbon-carbon bond formation reaction is occurred to generate 2-position alkyl or aromatic radical substituted Tanshinone I derivant (I), its In middle formula (I), Z is identical with the definition in logical formula (I) above, the most further gained compound derivatization is obtained other Formula (I) compound.
Above-mentioned bromination reaction is typically carried out in the presence of activated brominated reagent.Here brominated reagent can be but not It is limited to N-bromo-succinimide and bromine water.
Above-mentioned bromination reaction is carried out the most in a solvent.The solvent used can be but not limited to polar solvent.Such as DMF etc..
The reaction temperature of above-mentioned bromination reaction is generally 0 DEG C to 40 DEG C.Reaction generally can at room temperature be carried out.
The raw material of bromination reaction is Tanshinone I (TA).This raw material is to be extracted by crude drug to be isolated, can be in city Acquisition is bought on Chang.Organic boronic or borate used by carbon-carbon bond formation reaction all can commercially buy acquisition.
2-bromine Tanshinone I intermediate again with corresponding organic boronic or borate, in the presence of a catalyst, occur carbon-to-carbon Key-like becomes reaction to generate 2-position alkyl or aromatic radical substituted Tanshinone I derivant (I).
Carbon-carbon bond formation reaction is typically carried out in the presence of palladium catalyst.Here palladium catalyst can be but not limited to four (triphenylphosphine) palladium (Pd (PPh3)4), palladium (Pd (OAc)2, [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride (Pd (dppf)Cl2).
Organoboron reagent for carbon-carbon bond formation reaction typically requires use blocking group to except boric acid or borate Functional group in addition protects.Finally take off the blocking group of use.
Carbon-carbon bond formation reaction is typically carried out in the presence of alkali.Here alkali can be organic base or inorganic base.Such as: Potassium phosphate, sodium carbonate, Sodium ethylate, triethylamine etc..
Carbon-carbon bond formation reaction is typically carried out in a solvent.The solvent used includes but not limited to organic polar solvent.Example As: dichloromethane (DCM), oxolane (THF), DMF (DMF), dimethyl sulfoxide (DMSO) etc..
Carbon-carbon bond formation reaction is typically carried out in a heated condition.Reaction temperature depends on the activity of boron reaction reagent, one As at 50 DEG C to 160 DEG C.
Prepare 2-position alkyl or aromatic radical substituted Tanshinone I derivant (I) typically by the most general method operation.Will Tanshinone I reacts generation 2-bromine Tanshinone I with N-bromo-succinimide at room temperature at DMF (DMF). The general operation of carbon-carbon bond formation reaction can be, but not limited to: in DMF (DMF) solvent, puts into The 2-bromine Tanshinone I of proper ratio, palladium catalyst and alkali, it is possible to add the part of catalytic amount.Heated and stirred reaction 24 hours, then The product generated with organic solvent extraction, washes through washing and saturated common salt, be dried, concentrate, obtain crude product.Recycle silicon glue post or High performance liquid chromatograph purification, obtains pure product.
Conventional chemical conversion can be used for implementing the present invention.Those skilled in the art may decide that and turns for these chemistry Suitable chemical reagent, solvent, protection group and the reaction condition changed.Relevant information is described in R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989);T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for Organic Synthesis, John Wiley and Sons(1994);L.A.Paquette editor Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
Protection group refers to that those once connect active part (such as, hydroxyl or amino), prevents anti-by later of these parts The group that should disturb and can be removed by conventional method after the reaction.The example of hydroxyl protecting group includes but not limited to, alkyl, Benzyl, pi-allyl, trityl (that is, trityl group), acyl group (such as, benzoyl, acetyl group or HOOC-X "-CO-, X " be alkylidene, alkylene group, cycloalkylidene or arlydene), silicyl (such as, trimethyl silyl, silicohetane Alkyl and t-butyldimethylsilyl), alkoxy carbonyl, amino carbonyl (such as, Dimethylaminocarbonyl, methyl second ammonia Base carbonyl and phenyl amino carbonyl), alkoxyl-methyl, benzene methoxyl methyl and alkyl mercapto methyl.The example of amino protecting group include but It is not limited to, alkoxy carbonyl, alkanoyl, aryloxycarbonyl, the substituted alkyl of aryl etc..Hydroxyl and amino protecting group exist T.W.Greene and P.G..M.Wuts, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley and Sons (1991) discuss.Hydroxyl and amino protecting group all can be after the reaction by routines Method remove.
Specifically, in preferred formula (I) compound of the present invention, BS-TA-03, BS-TA-01, BS-TA-04, BS-TA- 06, BS-TA-07, BS-TA-09, BS-TA-14, BS-TA-41, BS-TA-31 are the pellet separated by natural extract with BS-TA-32 Ginseng ketone I (TA) is that raw material is prepared by above-mentioned two-step reaction.
BS-TA-301 obtains with BS-TA-31 for raw material carries out etherificate and open loop.
BS-TA-302 obtains through hydrolysis with BS-TA-32 for raw material.
BS-TA-306 and BS-TA-307 obtains with BS-TA-31 for raw material is esterified.
BS-TA-301 carries out being etherified and hydrolyzing and obtain with BS-TA-31 for raw material.
Present invention also offers the pharmaceutical composition comprising formula I.
The invention provides such pharmaceutical composition, wherein comprise the Formulas I of at least one present invention as above Compound, and optional pharmaceutically acceptable excipient.
The method preparing the various pharmaceutical composition containing a certain amount of active component is known, or according to the present invention's Disclosure will be readily apparent to one having ordinary skill.Such as REMINGTON ' S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995) are described.Prepare described pharmaceutical composition Method include mixing suitable pharmaceutical excipient, carrier, diluent etc..
Manufacture the pharmaceutical preparation of the present invention in a known way, including conventional mixing, dissolving or freeze drying process.
The compound of the present invention can make pharmaceutical composition, and be suitable for the various ways of the method for application selected to patient Footpath is used, the most oral or parenteral (by intravenous, intramuscular, local or subcutaneous route).
Therefore, the compound of the present invention combine pharmaceutically acceptable carrier (as inert diluent or assimilable can Edible carrier) can be with systemic administration, such as, oral.They can be enclosed in the hard or gelatine capsule of soft shell, can press and is Tablet.Using for oral medication, reactive compound can be in conjunction with one or more excipient, and with deglutible tablet, cheek Form containing tablet, buccal tablet, capsule, elixir, suspending agent, syrup, disk etc. uses.This compositions and preparation should comprise The reactive compound of at least 0.1%.The ratio of this compositions and preparation, it is of course possible to change, can account for given unit dosage forms About the 1% of weight is to about 99%.In the compositions that this treatment is useful, the amount of reactive compound makes it possible to acquisition to be had Effect dosage level.
Tablet, buccal tablet, pill, capsule etc. can also comprise: binding agent, as Tragacanth, arabic gum, corn starch or Gelatin;Excipient, such as dicalcium phosphate;Disintegrating agent, such as corn starch, potato starch, alginic acid etc.;Lubricant, such as stearic acid Magnesium;And sweeting agent, such as sucrose, fructose, lactose or aspartame;Or flavoring agent, such as Herba Menthae, wintergreen oil or cherry flavor.Work as list When position dosage form is capsule, except above types of material, it can also comprise liquid-carrier, such as vegetable oil or Polyethylene Glycol.Respectively Plant other materials can exist, as coating, or otherwise change the physical form of solid unit dosage form.Such as, tablet, Pill or capsule can use the coatings such as gelatin, wax, Lac or sugar.Syrup or elixir can comprise reactive compound, sucrose or Fructose is as sweeting agent, nipagin or propyl parabene as preservative, and dyestuff and flavoring agent are (as Fructus Pruni pseudocerasi is fragrant Material or orange flavor).Certainly, any material for preparing any unit dosage forms should be pharmaceutically acceptable and with should Amount the most nontoxic.Additionally, reactive compound can mix in slow releasing preparation and delayed release device.
Reactive compound can also be by infusion or be expelled to intravenous or intraperitoneal is used.Reactive compound can be prepared Or the aqueous solution of its salt, the optional nontoxic surfactant mixed.Can also prepare at glycerol, liquid macrogol, sweet Dispersant in oil triacetate and mixture and oil.Under the conditions of common storage and using, these preparations comprise anti- Rotten agent is to prevent growth of microorganism.
Be suitable to injection or the pharmaceutical dosage form of infusion can include comprising be suitable to aseptic injectable or can infusion solution or The aseptic aqueous solution of the active component (being optionally encapsulated in liposome) of the instant preparation of dispersant or dispersant or sterilized powder. In all cases, final dosage form is producing and must be aseptic, liquid and stable under condition of storage.Liquid-carrier Can be solvent or liquid dispersion medium, including, such as water, ethanol, polyhydric alcohol (such as, glycerol, propylene glycol, the poly-second of liquid two Alcohol etc.), vegetable oil, nontoxic glyceride and suitable mixture thereof.Suitable mobility can be maintained, such as, pass through lipid The formation of body, by maintaining required particle size, or by the use of surfactant in the case of dispersant.Can lead to Cross various antibacterial agent and antifungal (such as metagin, methaform, phenol, sorbic acid, thimerosal etc.) produces prevention The effect of microorganism.In many cases it is preferred to include isotonic agent, such as sugar, buffer agent or sodium chloride.By using delayed absorption The compositions (such as, aluminum monostearate and gelatin) of agent can produce the prolongation of injectable compositions and absorb.
By other compositions above-named various by the reactive compound of the requirement in suitable solvent Yu needs In conjunction with, then carry out filtration sterilization, prepare sterile injectable solution.Feelings at the sterilized powder for preparing aseptic injectable solution Under condition, preferred preparation method is vacuum drying and Freeze Drying Technique, and this can produce active component and additionally need plus any Former sterilefiltered solutions present in the powder of composition.
Useful solid carrier includes that the solid pulverized is (such as Talcum, clay, microcrystalline Cellulose, silicon dioxide, aluminium oxide Deng).Useful liquid-carrier includes water, ethanol or ethylene glycol or water-ethanol/ethylene glycol mixture, and the compound of the present invention can To be optionally dissolved or dispersed in wherein with effective content with the help of nontoxic surfactant.Adjuvant can be added (such as perfume (or spice) Taste) and other antimicrobial optimize the character for given purposes.
Thickening agent (polymer, fatty acid, soap and ester, fatty alcohol, modified cellulose or the modified inorganic such as synthesis Material) also can be used for forming paintable paste, gel, ointment, soap etc. with liquid-carrier, it is directly used in the skin of user On.
The treatment requirement of compound or its active salt or derivant, depends not only on the specific salt of selection, Er Qiequ Certainly in insecticide-applying way, the essence of disease to be treated and the age of patient and state, ultimately depend on doctor on the scene or clinical doctor Raw decision.
Above-mentioned preparation can exist with unit dosage forms, and this unit dosage forms is the physical dispersion unit containing unit dose, suitable In being administered to human body and other mammalian body.Unit dosage forms can be capsule or tablet, or much capsule or tablets.According to Involved concrete treatment, the amount of the unit dose of active component can be between about 0.1 to about 1000 milligrams or more It is changed or adjusts.
Compound that the present invention also provides for the present invention or the compositions that comprises this compound are preparing medicine, particularly anti-swollen Purposes in tumor medicine.Correspondingly, the present invention provides a kind of method treating tumor patient, including giving to need the patient for the treatment of The compound of at least one present invention of therapeutically effective amount.The 2-position alkyl of the present invention or the substituted Tanshinone I of aromatic radical derive Thing or its pharmaceutically acceptable salt such as can be used for treating leukemia, multiple myeloma, lymphoma, hepatocarcinoma, gastric cancer, mammary gland Cancer, cholangiocellular carcinoma, cancer of pancreas, pulmonary carcinoma, colorectal cancer, osteosarcoma, melanoma, human cervical carcinoma, glioma, nasopharyngeal carcinoma, The tumors such as laryngeal carcinoma, the esophageal carcinoma, middle ear neoplasms, carcinoma of prostate.
In the examples below that, the present invention will more specifically be explained.It should be understood that the following example is intended to this is described Bright and not to the scope of the present invention constitute any restriction.
Chemical raw material used in following example is commercially available or is obtained by synthetic method well known in the art.
Embodiment 1: the synthesis of compound (BS-TA-03)
In formula, DMF:N, dinethylformamide;NBS:N-bromo-succinimide;
2-Bromotanshinone:2-bromine Tanshinone I
Tanshinone I (1g, 3.6mmol), N-bromo-succinimide is added in DMF (30mL) (0.67g, 3.78mmol), after being stirred at room temperature 3 hours, filters the precipitation generated, and filtering residue is through washing, saturated sodium bicarbonate solution Wash, be dried to obtain 2-bromine Tanshinone I (0.82g, yield 63.8%).
In formula: CH3B(OH)2: methyl-boric acid;K3PO4: potassium phosphate;Pd(PPh3): tetrakis triphenylphosphine palladium
Under nitrogen protective condition, add in the DMF (10mL) 2-bromine Tanshinone I (100mg, 0.28mmol), methyl-boric acid (20mg, 0.34mmol), potassium phosphate (148mg, 0.7mmol), it is subsequently added four (triphenylphosphines) Palladium (388mg, 0.34mmol), is heated to 100 DEG C, after stirring 16 hours, adds water, extract with dichloromethane in reactant liquor Taking, organic facies is washed through saturated sodium bicarbonate solution, and anhydrous sodium sulfate is dried, the thick product obtained after concentration, divides through preparative hplc From obtaining black solid compound BS-TA-03 (5.9mg, yield 8%) after purification.
LC-MS: retention time: 3.10min (98.6%);M/z:291.1 (M+H).
1H NMR (300MHz, CDCl3) δ 9.220 (d, 1H), 8.246 (d, 1H), 7.749 (d, 1H), 7.528 (m, 1H), 7.337 (m, 1H), 2.680 (s, 3H), 2.332 (s, 3H), 2.191 (s, 3H).
According to the method for BS-TA-03, use above-mentioned same reagent, by anti-with phenylboric acid for compound 2-bromine Tanshinone I Should, it is prepared for BS-TA-01:
LC-MS: retention time: 3.40min (99.07%), m/z:353.0 (M+H).
According to the method for BS-TA-03, use above-mentioned same reagent, by compound 2-bromine Tanshinone I and 2-chlorphenyl boron Acid reaction, is prepared for BS-TA-04:
LC-MS: retention time: 3.44min (99.62%), m/z:387.0 (M+H).
1H NMR (300MHz, CDCl3) δ 9.271 (d, 1H), 8.333 (d, 1H), 7.895 (d, 1H), 7.575 (m, 3H), 7.444 (m, 3H), 2.702 (s, 3H), 2.318 (s, 3H).
According to the method for BS-TA-03, use above-mentioned same reagent, by compound 2-bromine Tanshinone I and 3,4-dimethyl Acid reaction, is prepared for BS-TA-06:
LC-MS: retention time: 3.60min (98.2%), m/z:381.0 (M+H).
According to the method for BS-TA-03, use above-mentioned same reagent, by compound 2-bromine Tanshinone I and 2-methoxyl group- Phenylboric acid reacts, and is prepared for BS-TA-07:
LC-MS: retention time: 3.30min (98.51%), m/z:383.0 (M+H).
According to the method for BS-TA-03, use above-mentioned same reagent, by compound 2-bromine Tanshinone I and 2-methoxyl group pyrrole Piperidinyl-3-acid reaction, is prepared for BS-TA-09:
LC-MS: retention time: 3.20min (98.82%), m/z:384.0 (M+H).
According to the method for BS-TA-03, use above-mentioned same reagent, by anti-with ethyl-boron dihydroxide for compound 2-bromine Tanshinone I Should, it is prepared for BS-TA-14:
LC-MS: retention time: 3.20min (94.36%), m/z:305.2 (M+H).
According to the method for BS-TA-03, use above-mentioned same reagent, by compound 2-bromine Tanshinone I and 3-pyridine boronic acid Reaction, is prepared for BS-TA-41:
LC-MS: retention time: 2.80min (98.75%), m/z:354.0 (M+H).
Embodiment 2: the synthesis of compound (BS-TA-31)
Under nitrogen protection atmosphere, add in the DMF (50mL) 2-bromine Tanshinone I (1.2g, 3.4mmol), 4-hydroxy benzenes boric acid (2.4g, 17.0mmol), sodium carbonate (2.1g, 20.3mmol), it is subsequently added four (triphenyls Phosphine) palladium (781mg, 0.7mmol), it is heated to 90 DEG C, after stirring 16 hours, in reactant liquor, adds water (200mL), with two Chloromethanes (100mL*4) extracts, and organic facies is washed through saturated sodium bicarbonate solution (200mL*4), and anhydrous sodium sulfate is dried, after concentration The thick product washing with alcohol obtained, obtains brown solid compound BS-TA-31 (800mg, yield 58%).
Embodiment 3: the synthesis of compound (BS-TA-301)
In formula, TsCl: paratoluensulfonyl chloride;Et3N: triethylamine;DMAP:4-dimethylamino naphthyridine
At 0 DEG C, to dissolved with compound 1 (1g, 7.6mmol) dichloromethane (20mL) in add triethylamine (1.1g, 11.3mmol), paratoluensulfonyl chloride (1.5g, 7.9mmol), DMAP (185mg, 1.5mmol).Reactant liquor room temperature Lower stirring added dichloromethane (100mL) after 12 hours, and water (20mL) dilutes, with 1N salt acid for adjusting pH to 3, and dichloromethane (50mL*3) extraction, merges organic facies, and organic facies is dried through anhydrous sodium sulfate, obtains compound 2 (2g, yield after concentration 95%).
Potassium carbonate is added in the DMF (2mL) dissolved with BS-TA-31 (150mg, 0.4mmol) (141mg, 1.0mmol), compound 2 (140mg, 0.5mmol), reactant liquor is heated to 80 DEG C, stirs 24 hours.Reaction knot Adding dichloromethane (100mL) extraction after bundle, organic facies is through washing (50mL*4), and anhydrous sodium sulfate is dried, and is changed after concentration Compound 3 (200mg, yield 100%), this crude product is the most purified is directly used in next step reaction.
To dissolved with dichloromethane (40mL) solution of compound 3 (200mg, 0.4mmol) drips oxolane/water (70%V/V) (2mL), reactant liquor is heated to 45 DEG C, after stirring 1 hour, is cooled to room temperature.Reactant liquor adds water (10mL), dichloromethane (50mL*4) extracts, and merges organic facies, is dried with anhydrous sodium sulfate, and the thick product obtained after concentration is used Washing with alcohol, obtains brown solid compound BS-TA-301 (73mg, yield 50%).
LC-MS: retention time: 1.93min (92.7%);M/z:443.2 (M+H).
1H NMR (300Hz, DMSO d-6) δ 9.123 (d, 1H), 8.375 (d, 1H), 7.928 (d, 1H), 7.706 (d, 2H), 7.557 (m, 1H), 7.386 (d, 1H), 7.112 (d, 2H), 5.016 (d, 1H), 4.722 (m, 1H), 4.096 (m, 1H), 3.952 (m, 1H), 3.841 (m, 1H), 3.489 (m, 2H), 2.636 (s, 3H), 2.401 (s, 3H).
Embodiment 4: the synthesis of compound (BS-TA-32)
2-bromine Tanshinone I (200mg, 0.56mmol), 4-methoxycarbonyl group is added in DMF (10mL) Phenylboric acid (507mg, 2.8mmol) and sodium carbonate (358mg, 3.4mmol), subsequently, add four (triphens under nitrogen protective condition Base phosphine) palladium (65mg, 0.056mmol).Reactant liquor is heated to 90 DEG C, stirring reaction 16 hours.After reaction terminates, to reaction Liquid adds water (100mL), extracts with dichloromethane (50mL*4), merge organic facies, through saturated sodium bicarbonate solution (100mL* 4) washing, anhydrous sodium sulfate is dried, and the thick product obtained after concentration obtains brown solid after silica gel chromatographic column purifies and separates Compound BS-TA-32 (140mg, yield 61%).
Embodiment 5: the synthesis of compound (BS-TA-302)
In formula: LiOH: Lithium hydrate
In DMF (20mL), the mixed solution of water (4mL) add BS-TA-32 (100mg, 0.24mmol), Lithium hydrate (40mg, 0.96mmol) it is subsequently added. reactant liquor stirring at normal temperature 18 hours.Reaction removes after terminating DMF solvent, reactant liquor trifluoroacetic acid/water (70%) regulation pH to 3~4, the solid second being filtrated to get Alcohol washs, and obtains brown solid compound BS-TA-302 (37mg, yield 37%).
LC-MS: retention time 1.657min;M/z:397 (M+H);
1H NMR (300Hz, DMSO d-6) δ 13.153 (s, 1H), 8.172-7.916 (m, 5H), 7.804 (d, 2H), 7.535 (m, 2H), 2.716 (s, 3H), 2.553 (s, 3H).
Embodiment 6: the synthesis of compound (BS-TA-306)
In DMF (2mL), add BS-TA-31 (50mg, 0.14mmol), be subsequently added potassium carbonate (56mg, 0.41mmol), succinic anhydrides (15mg, 0.15mmol), reactant liquor stirring at normal temperature is overnight.After reaction terminates, add water (10mL), extracting with dichloromethane (20mL*3), merge organic facies, through washing, anhydrous sodium sulfate is dried, and obtain after concentration is thick Product obtains brown solid compound BS-TA-306 (30mg, yield 48%) after preparing thin layer chromatography and separating.
LC-MS: retention time 1.547min;M/z:469 (M+H);
1H NMR (300Hz, DMSO d-6) δ 9.997 (s, 1H), 8.758 (d, 1H), 8.449 (m, 1H), 7.919 (m, 1H), 7.642-7.519 (m, 3H), 7.423 (m, 1H), 6.952-6.907 (m, 2H), 3.869 (m, 1H), 3.685 (m, 1H), 2.904 (m, 1H), 2.730 (s, 3H), 2.174 (s, 3H), 1.229 (s, 2H), 0.850 (m, 1H).
Embodiment 7: the synthesis of compound (BS-TA-307)
In DMF (2mL), add BS-TA-31 (70mg, 0.20mmol), be subsequently added potassium carbonate (79mg, 0.57mmol), glutaric anhydride (33mg, 0.29mmol), reactant liquor stirring at normal temperature is overnight.After reaction terminates, add water (10mL), extracting with dichloromethane (20mL*3), merge organic facies, through washing, anhydrous sodium sulfate is dried, and obtain after concentration is thick Product obtains red solid compound BS-TA-307 (25mg, yield 28%) after preparing thin layer chromatography and separating.
LC-MS: retention time 1.530min;M/z:483 (M+H);
1H NMR (300Hz, DMSO d-6) δ 9.989 (s, 1H), 8.533-8.423 (dd, 2H), 7.880 (m, 1H), 7.636-7.532 (m, 3H), 7.414 (d, 1H), 6.925 (d, 2H), 3.156-3.132 (m, 1H), 2.905-2.876 (m, 2H), 2.726-2.685 (m, 4H), 2.233 (s, 3H), 1.991 (m, 1H), 1.905 (m, 1H).
Embodiment 8: the synthesis of compound (BS-TA-309)
In DMF (2mL), add BS-TA-31 (100mg, 0.27mmol), be subsequently added potassium carbonate (113mg, 0.82mmol), bromoacetate (68mg, 0.41mmol), sodium iodide (65mg, 0.43mmol), reactant liquor heating rises Temperature is to 80 DEG C, and stirring is reacted 24 hours.After reaction terminates, in reactant liquor, add dichloromethane (100mL), through washing, be dried, The thick product that obtains after concentration is the most purified is directly used in next step reaction.
Add in DMF (20mL), the mixed solution of water (4mL) compound 4 (120mg, 0.26mmol), Lithium hydrate (44mg, 1.1mmol) it is subsequently added. reactant liquor stirring at normal temperature 18 hours.Reaction removes after terminating DMF solvent, reactant liquor trifluoroacetic acid/water (70%) regulation pH to 3~4, the solid second being filtrated to get Alcohol washs, and obtains brown solid compound BS-TA-309 (40mg, yield 37%).
LC-MS: retention time 1.578min;M/z:427 (M+H);
1H NMR (300Hz, DMSO d-6) δ 9.147 (d, 1H), 8.427 (d, 1H), 7.986 (d, 1H), 7.722 (d, 3H), 7.419 (d, 1H), 7.064 (d, 2H), 4.638 (s, 2H), 2.720 (s, 2H), 2.386 (s, 3H).
Embodiment 9: the 2-position alkyl of the present invention or the aromatic radical substituted Tanshinone I antileukemie determination of activity of derivant
(1) experiment material
Leukemia cell line: K562/adr (drug resistance chronic myelogenous leukemia, CML), NB4 (the white blood of acute progranulocyte Disease, AML), Kasumi-1 (acute myeloid leukemia M2 type, AML-M2), Jurkat (acute lymphoblastic leukemia, ALL), with Upper cell line is all given in institute of oncology of Zhejiang University;H9 (acute lymphoblastic leukemia, ALL), trains purchased from Chinese Typical Representative Support thing preservation center.
Reagent: Tanshinone I (TA) standard substance are purchased from Man Site bio tech ltd, Chengdu (Sichuan), the 2-of the present invention Position alkyl or aromatic radical substituted Tanshinone I derivant.
Key instrument: Thermo Scientific 3111 cell culture incubator, Bio-Rad iMark microplate reader
(2) experimental technique
Tanshinone I (TA) standard substance and the 2-position alkyl of the present invention or aromatic radical substituted Tanshinone I derivant, use diformazan Base sulfoxide fully dissolves, and is made into the mother solution of 10mg/mL, puts 4 DEG C of refrigerators and keeps in Dark Place, and is diluted to institute with cell culture fluid before experiment Need concentration.
Take well-grown leukaemia 6000, be inoculated into 96 porocytes and cultivate in plate hole.Culture fluid is containing 10% The RPMI-1640 cell culture fluid of hyclone.The 2-position alkyl adding variable concentrations in second day or the substituted Radix Salviae Miltiorrhizae of aromatic radical Ketone I derivant, after mixing, is placed in carbon dioxide (5%CO2) cell culture incubator 37 DEG C cultivate 72 hours.Then measure with mtt assay Viable cell concentrations.Matched group (being not added with compound treatment) cell viability is set to 100% in this experiment, and calculates compound work With rear cell viability (%) and 72 hours leukaemia's half growth inhibitory concentration (72 hours IC50Value, μ g/mL).
(3) experimental result
Experimental result is shown in Table 1.
Table 1 shows that the 2-position alkyl of the present invention or aromatic radical substituted Tanshinone I derivant can induce major part leukemia Cell grows.Compare with Tanshinone I itself, the 2-position alkyl of the present invention or aromatic radical substituted Tanshinone I derivant BS-TA- 302 anti-NB4 (acute promyelocytic leukemia) and H9 (acute lymphoblastic leukemia) activity improves nearly 5 times;BS-TA- 301 anti-Jurkat (acute lymphoblastic leukemia) activity improve more than 3 times.
Leukemia cell growth inhibition concentration is measured by table 1:2-position alkyl or aromatic radical substituted Tanshinone I derivant (72 hours, IC50(μ g/mL) value and IC90(μ g/mL) value).
Embodiment 10: the 2-position alkyl of the present invention or the aromatic radical substituted Tanshinone I anti-human multiple myeloma of derivant Cytoactive detection
(1) experiment material
Myeloma cell strain: RPMI 8226 (multiple myeloma), purchased from Fu Xiang bio tech ltd, Shanghai.
Reagent: with embodiment 9
Key instrument: Thermo Scientific 3111 cell culture incubator, Bio-Rad iMark microplate reader.
(2) experimental technique
Tanshinone I (TA) standard substance and the 2-position alkyl of the present invention or aromatic radical substituted Tanshinone I derivant, use diformazan Base sulfoxide fully dissolves, and is made into the mother solution of 10mg/mL, puts 4 DEG C of refrigerators and keeps in Dark Place, and is diluted to institute with cell culture fluid before experiment Need concentration.
Take well-grown above-mentioned tumor cell 6000, be inoculated into 96 porocytes and cultivate in plate hole.Culture fluid is for containing The RPMI-1640 cell culture fluid of 10% hyclone.The 2-position alkyl or the aromatic radical that within second day, add variable concentrations are substituted Tanshinone I derivant, after mixing, is placed in carbon dioxide (5%CO2) cell culture incubator 37 DEG C cultivate 72 hours.Then mtt assay is used Measure viable cell concentrations.Matched group (being not added with compound treatment) cell viability is set to 100% in this experiment, and calculates chemical combination Cell viability (%) and 72 hours leukaemia's half growth inhibitory concentration (72 hours IC after thing effect50Value, μ g/mL).
(3) experimental result
Experimental result is shown in Table 2.
Table 2 shows compared with Tanshinone I derivant BS-TA-301 and Tanshinone I of the present invention itself, anti-RPMI8226 cell Strain activity is significantly improved, can effective inducing human bone marrow oncocyte death and suppression growth of tumour cell.
Embodiment 11: 2-position alkyl of the present invention or aromatic radical substituted Tanshinone I derivant anti-human solid tumor effect measure
(1) experiment material
Human solid tumor's cell strain:
Hep-2 (laryngeal carcinoma), A549 (people's pulmonary carcinoma), CaEs-17 (esophageal cancer cell), PC-3 (carcinoma of prostate), CNE (nasopharynx Cancerous cell), SK-OV-3 (ovarian cancer cell) be purchased from China typical culture collection center;RKO (human colon adenocarcinoma cell), MGC-803 (gastric carcinoma cells), MG-63 (osteosarcoma), U87-MG (malignant glioma cell) are purchased from the multiple auspicious biology in Shanghai Science and Technology Ltd.;PANC-1 (cancer of pancreas), Becap-37 (human breast cancer cell), Hela (human cervical carcinoma cell), Hep G2 (human liver cancer cell) is all given in institute of oncology of Zhejiang University.
Reagent: with embodiment 9
Key instrument: Thermo Scientific 3111 cell culture incubator, Bio-Rad iMark microplate reader.
(2) proved recipe method is bought
Tanshinone I (TA) standard substance and the 2-position alkyl of the present invention or aromatic radical substituted Tanshinone I derivant, use diformazan Base sulfoxide fully dissolves, and is made into the mother solution of 10mg/mL, puts 4 DEG C of refrigerators and keeps in Dark Place, and is diluted to institute with cell culture fluid before experiment Need concentration.
Take 6000, well-grown human solid tumor's cell, be inoculated into 96 porocytes and cultivate in plate hole.Culture fluid is for containing The DMEM height sugar cell culture fluid of 10% hyclone.It is placed in carbon dioxide (5%CO2) cell culture incubator 37 DEG C cultivates 24 little Time, then, add 2-position alkyl or the aromatic radical substituted Tanshinone I derivant of variable concentrations, after mixing, continue to put titanium dioxide Carbon (5%CO2) cell culture incubator 37 DEG C cultivate 72 hours.Then viable cell concentrations is measured with mtt assay.Matched group in this experiment (being not added with compound treatment) cell viability is set to 100%, and calculate after compound effects cell viability (%) and 72 hours white Disorders of blood cell half growth inhibitory concentration (72 hours IC50Value).
(3) experimental result
Experimental result is shown in Table 2.
Table 2 shows that the 2-position alkyl of the present invention or aromatic radical substituted Tanshinone I derivant can be induced to a certain extent Human solid tumor's cell death and these growth of tumour cell of suppression.Wherein the 2-position substituted Tanshinone I of alkyl of the present invention derives Thing BS-TA-301, BS-TA-302 are particularly evident, anti-Becap-37 (human breast cancer cell), Hela (human cervical carcinoma cell), Hep G2 (human liver cancer cell), RKO (human colon adenocarcinoma cell), U87-MG (malignant glioma cell), SK-OV-3 (ovary Cancerous cell) all show the broad-spectrum anti-tumor activity being better than Tanshinone I itself on cell strain;Additionally, BS-TA-301 is at CNE (nose Pharyngeal cancer cell) on also show preferable anti-tumor activity;BS-TA-302 is in MGC-803 (gastric carcinoma cells), PC-3 (prostatitis Adenocarcinoma) on, compared with Tanshinone I itself, activity all has more apparent raising;BS-TA-03 anti-RKO (human colon adenocarcinoma cell), Preferable activity is also show on CNE (nasopharyngeal carcinoma cell) and PC-3 (carcinoma of prostate) cell strain;BS-TA-04 is at anti-U87-MG On (malignant glioma cell) cell strain, activity is also superior to Tanshinone I itself.
Human solid tumor's cell growth inhibition concentration is measured by table 2:2-position alkyl or aromatic radical substituted Tanshinone I derivant (72 hours, IC50(μ g/mL) value and IC90(μ g/mL) value).
Table 2 (Continued)
Table 2 (Continued)
Table 2 (Continued)

Claims (16)

1. lead to Tanshinone I derivant or its pharmaceutically acceptable salt of formula (I),
Work as Z=R, for the Tanshinone I of Formulas I-1;Work as Z=Ar, for the Tanshinone I of Formulas I-2;
Wherein R is selected from C1-C18Alkyl, C2-C18Alkenyl or alkynyl;Ar is selected from replacement or unsubstituted phenyl;Wherein said replacement Be be selected from lower group one or more substituent groups replace: halogen, amino, C1-C6Alkyl-substituted amino, nitro, cyano group, C1-C6 Alkoxyl, sulfydryl, C1-C6Alkylthio group, or water soluble functional group;Ar also can be by C1-C6Alkyl replaces;Described water soluble group Functional group is selected from hydroxyl, multi-hydroxy alkoxy, saccharide residue, carboxyl, sulfonic group, phosphate, multi-hydroxy alkoxy carbonyl, carboxyl alkane Epoxide, carboxyalkyl formyloxy, alkoxyl and alkyl in wherein said group each have 1-8 carbon atom.
Tanshinone I derivant the most according to claim 1 or its pharmaceutically acceptable salt, wherein R is C1-C6Alkyl.
Tanshinone I derivant the most according to claim 2 or its pharmaceutically acceptable salt, wherein R is methyl.
Tanshinone I derivant the most according to claim 1 or its pharmaceutically acceptable salt, wherein Ar is the benzene of halogen substiuted Base.
Tanshinone I derivant the most according to claim 4 or its pharmaceutically acceptable salt, wherein Ar is the substituted phenyl of chlorine.
Tanshinone I derivant the most according to claim 1 or its pharmaceutically acceptable salt, wherein Ar is C1-C6Alkoxyl replaces Phenyl.
Tanshinone I derivant the most according to claim 6 or its pharmaceutically acceptable salt, wherein Ar is methoxyphenyl.
Tanshinone I derivant the most according to claim 1 or its pharmaceutically acceptable salt, wherein Ar be multi-hydroxy alkoxy or The substituted phenyl of saccharide residue.
Tanshinone I derivant the most according to claim 8 or its pharmaceutically acceptable salt, wherein said multi-hydroxy alkoxy has There is 3-7 carbon atom;Described saccharide residue has 3-7 carbon atom.
Tanshinone I derivant the most according to claim 9 or its pharmaceutically acceptable salt, wherein said multi-hydroxy alkoxy For glycerol residue;Described saccharide residue is glucose residue.
11. Tanshinone I derivant according to claim 1 or its pharmaceutically acceptable salts, wherein Ar be carboxyl, sulfonic group or The substituted phenyl of phosphate.
12. Tanshinone I derivant according to claim 1 or its pharmaceutically acceptable salts, selected from following compound:
2-methyl-Tanshinone I
2-Chloro-O-Phenyl-Tanshinone I
2-o-methoxyphenyl-Tanshinone I
2-ethyl-Tanshinone I
2-(4-(2,3-dihydroxy the third oxygen)) phenyl-Tanshinone I
To formic acid phenyl-Tanshinone I.
13. 1 kinds of methods preparing formula (I) compound
Including by Tanshinone I (TA) first through bromination reaction, generate 2-bromine Tanshinone I intermediate;This intermediate has with corresponding again Machine boric acid or borate, in the presence of a catalyst, occur carbon-carbon bond formation reaction to generate Tanshinone I derivant (I), its Chinese style (I) in, Ζ is identical with the definition in logical formula (I) in any one of claim 1-12.
14. 1 kinds of pharmaceutical compositions, wherein comprise the Tanshinone I derivant any one of claim 1-12 or it pharmaceutically may be used The salt accepted and optional pharmaceutically acceptable excipient.
Tanshinone I derivant or its pharmaceutically acceptable salt of any one in 15. claim 1-12 are preparing antitumor Purposes in medicine, described tumor selected from from leukemia, multiple myeloma, hepatocarcinoma, gastric cancer, breast carcinoma, cancer of pancreas, pulmonary carcinoma, Colorectal cancer, osteosarcoma, human cervical carcinoma, nasopharyngeal carcinoma, laryngeal carcinoma, the esophageal carcinoma, carcinoma of prostate, ovarian cancer and malignant glioma.
16. intermediate compound of formula,
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109369771A (en) * 2018-10-09 2019-02-22 深圳市第二人民医院 A kind of synthesis and application of tanshinone IIA derivative

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1837199A (en) * 2006-04-26 2006-09-27 秦引林 Tanshinone I derivatives and pharmaceutical application thereof
CN1837200A (en) * 2006-04-26 2006-09-27 秦引林 Tanshinone I derivatives and pharmaceutical application thereof
CN101012270A (en) * 2007-01-26 2007-08-08 广东工业大学 Tanshinone derivative and its application in preparing aldose reduction enzyme inhibitor pharmaceutical
US20070207989A1 (en) * 2006-03-03 2007-09-06 Savipu Pharmaceuticals Diterpene derivatives for the treatment of cardiovascular, cancer and inflammatory diseases

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090073381A (en) * 2007-12-31 2009-07-03 주식회사 머젠스 Pharmaceutical composition for the treatment and prevention of cardiac disease

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070207989A1 (en) * 2006-03-03 2007-09-06 Savipu Pharmaceuticals Diterpene derivatives for the treatment of cardiovascular, cancer and inflammatory diseases
CN1837199A (en) * 2006-04-26 2006-09-27 秦引林 Tanshinone I derivatives and pharmaceutical application thereof
CN1837200A (en) * 2006-04-26 2006-09-27 秦引林 Tanshinone I derivatives and pharmaceutical application thereof
CN101012270A (en) * 2007-01-26 2007-08-08 广东工业大学 Tanshinone derivative and its application in preparing aldose reduction enzyme inhibitor pharmaceutical

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
丹参二萜醌的结构修饰;杨东 等;《中国药科大学学报》;19980830;第29卷(第4期);第255-258页,参见第256-257页 *
丹参酮化合物对 HeLa细胞抑制作用与构效关系探讨;叶因涛 等;《医药导报》;20091031;第28卷(第10期);第1261-1264页 *
丹参酮类化合物对SPC-A-1细胞的生长抑制及其构效关系探讨;石华月 等;《中国肺癌杂志》;20110131;第14卷(第1期);第7-12页 *
丹参酮类及有关化合物抑菌作用的构效关系;罗厚蔚 等;《中国药科大学学报》;19880609;第19卷(第4期);第258-262页,参见第261页化合物19 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109369771A (en) * 2018-10-09 2019-02-22 深圳市第二人民医院 A kind of synthesis and application of tanshinone IIA derivative

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